Carboplatinum

Carboplatinum is one of a series of Platinum compounds ^Ynthesised with the aim of finding a Cisplatinum ana?9ue with equivalent or superior anti-tumour activity "ut reduced renal toxicity and less emetic activity. Cisplatinum was first used in clinical studies in the early 1970's and is established as essential in the treatment of malignant germ cell tumours particularly teratoma. It is, however, associated with severe toxicity: in Particular renal, (raised creatinine in 20% patients); Peripheral neuropathy in >20%; ototoxicity in 20%, and severe nausea and vomiting which are difficult to control even with high dose antiemetic combinations. Ever since lts clinical usefulness was confirmed the search has been ?n for a platinum compound with equivalent therapeutic icacy but less toxicity.


INTRODUCTION
Carboplatinum is one of a series of Platinum compounds ^Ynthesised with the aim of finding a Cisplatinum ana-?9ue with equivalent or superior anti-tumour activity "ut reduced renal toxicity and less emetic activity.
Cisplatinum was first used in clinical studies in the early 1970's and is established as essential in the treatment of malignant germ cell tumours particularly teratoma. It is, however, associated with severe toxicity: in Particular renal, (raised creatinine in 20% patients); Peripheral neuropathy in >20%; ototoxicity in 20%, and severe nausea and vomiting which are difficult to control even with high dose antiemetic combinations. Ever since lts clinical usefulness was confirmed the search has been ?n for a platinum compound with equivalent therapeutic icacy but less toxicity. a) It is more stable in human plasma leading to less irreversible protein binding. b) More carboplatinum is excreted by glomerular filtration a greater percentage of a given dose is present in the urine and hence a smaller percentage of total platinum remains in the body. c) The terminal half life of free non-protein bound platinum is approximately ten times that of cis platinum. d) The terminal half life of total platinum is measurable in hours and is approximately fifteen times shorter than that of cisplatinum.

Excretion
The major route of excretion is via the kidney and total body and renal clearances of free platinum correlate with the Glomerular Filtration Rate (GFR). In man, as observed in animals, and in contrast to cis platinum, there does not appear to be any tubular secretion. Phase I studies have indicated that toxicities correlate well with creatinine clearance and that the percentage reduction in platelet count correlates highly and linearly with the area under the curve of plasma ultrafilterable platinum. A more predictable myelosuppression is obtained by correlating the dose with GFR.

Pre-clinical studies
Pre-clinical studies of carboplatinum showed activity comparable to cis-platinum in many tumour lines, superior in some and less in a few.

Clinical Studies
Phase I and II studies were done at the Royal Marsden Hospital from 1981. 69 patients were entered into a Phase I study1, 16 of whom had renal impairment. There was no evidence of nephrotoxicity or ototoxicity, nausea and vomiting were less than with cis platinum, and the dose limiting factor was myelosuppression. Phase III studies in adults2: carboplatinum has been compared with cisplatinum in a randomised study of women with ovarian carcinoma. Its reduced toxicity and equivalent therapeutic benefit was confirmed.
Dosage escalation studies in patients with stage IV ovarian carcinoma have also been done3. The principal toxicities were bone marrow suppression, particularly thrombocytopenia and nausea and vomiting. No neurotoxicity was seen and alopecia was rare. Bristol Children's Hospital Study From April 1986, selected patients with poor prognosis tumours or who had relapsed, were entered into the Bristol Children's Hospital Resistant Tumour Protocol (BCH RTP) below.
BCH RESISTANT TUMOUR-PROTOCOL I 1. Vincristine 1.5mgs/m2 (max 2mg) weekly x 7 doses during the first cycle, than every 3 weeks. 2,3, and 4 given at three week intervals (9 week cycle)x5. Carboplatinum is the third arm of this protocol and is given at a dose of 500 mg/m2 in combination with vincristine 1.5mg/m2, 3 weeks after Epirubicin.
Between September 1985 and January 31st 1987, 14 patients aged between 4 and 17 have been treated with 39 courses of carboplatinum. In 12, the carboplatinum was given as part of the BCH RTP above. The first 2 patients received carboplatinum at doses of 300 mg/m2 and 400 mg/m2 respectively prior to the commencement of the protocol.
Five of the 14 had received prior chemotherapy. The diagnoses and characteristics of the patients are listed in Table 1.

Method of Administration
After full blood count and creatinine measurements, the vincristine is given as an i.v. push and carboplatinum is then added to 100 ml of 5% dextrose and given over 1 hour. It is given on an outpatient basis with an i.v. anti-emetic given at the end of the infusion and a supply of anti-emetics (usually suppositories) given to the patients for subsequent use as required. Most patients go home the same day, though a few elect to remain in hospital overnight because of vomiting.
Full blood counts are done at approximately 10 days and biochemical investigations, including creatinine, LFTs calcium and magnesium prior to the next course of chemotherapy. Audiograms were carried out where possible before each course.

Toxicity a) Haematological
There was remarkably little haematological toxicity with nadir neutrophil counts falling below 1 x 109/L on only 4 occasions and the nadir platelet count below 100x109L on 7 occasions. Table 2 shows the nadir values for total white count, neutrophils and platelets.  Table 3 shows the time in days for nadir to be reached. was late for the platelet count, more than half the Pa' tients actually experiencing their nadir platelet count3 the time of their next chemotherapy. This led to trea1' ment delays in 5 out of 39 courses?2 for neutropenia and 3 for thrombocytopenia. Carboplatinum Day 0, nadir and pre-treatment total ^f(j neutrophil count and platelet count with means and stand3 deviations. Figure 1 Carboplatinum Day 0, nadir and pre-treatment total neutrophil count and platelet count with means and stand3 deviations. 2-10 hours at home. Appetite returned to normal after aPproximately 36-48 hours. Renal child who had not previously received cis platinum had evidence of renal toxicity as measured by serial serum creatinine levels. One child, previously treated ^'th cis platinum to a total dose of 420 mg 3 years Prior to carboplatinum, had grade I (WHO) elevation ?f serum creatinine at the completion of 4 cycles of Carboplatinum at 300mg/m2 in December 1985. By j^nuary 1987 51CrEDTA clearance showed his GFR to ?e marginally reduced. Serum magnesium has been Measured after 17 courses and there has been no Eduction.
^udiological 'here was no demonstratable change in audiograms done on patients on the protocol. The child who had had previous cis platinum therapy had bilateral high frequency loss which has remained stable since carboplatinum therapy was completed 15 months ago. Liver }"here was no evidence of liver toxicity as measured bV changes in liver function tests such as bilirubin and asPartate transaminase. CONCLUSIONS Carboplatinum can be given to children at a dose of 500mg/m2, on an out-patient basis, is reasonably well tolerated (vomiting can usually be managed by parents at home) and does not cause unacceptable haematological toxicity. There was no evidence in these patients of renal, hepatic or ototoxicity. Alopecia was already present in all patients and so it is not possible for us to evaluate this though it was reported to be rare in one adult study.